1.Simultaneous targeting of 5-LOX-COX and EGFR blocks progression of pancreatic ductal adenocarcinoma.
Rao CV1, Janakiram NB1, Madka V1, Devarkonda V1, Brewer M1, Biddick L1, Lightfoot S1, Steele VE2, Mohammed A1. Oncotarget. 2015 Oct 20;6(32):33290-305. doi: 10.18632/oncotarget.5396.
Cyclooxygenase-2 (COX-2), 5-Lipoxygenase (5-LOX), and epidermal growth factor receptor (EGRF) are over-expressed in human pancreatic ductal adenocarcinoma (PDAC). Using next-generation sequencing (NGS) analysis, we show significant increase in COX-2, 5-LOX, and EGFR expression during PDAC progression. Targeting complementary pathways will achieve better treatment efficacy than a single agent high-dose strategy that could increase risk of side effects and tumor resistance. To target COX-2, 5-LOX, and EGFR simultaneously, we tested effects of licofelone (dual 5-LOX-COX inhibitor), and gefitinib (EGFR inhibitor), individually and in combination, on pancreatic intraepithelial neoplasms (PanINs) and their progression to PDAC using genetically engineered mice. Individually, licofelone (L) and gefitinib (G) significantly inhibited incidence of PDAC in male (72% L, 90% G, p < 0.0001) and female (90% L, 85% G, p < 0.0001) mice. The combination drug treatment produced complete inhibition of PDAC in both genders.
2.Inhibition of 5-LOX, COX-1, and COX-2 increases tendon healing and reduces muscle fibrosis and lipid accumulation after rotator cuff repair.
Oak NR1, Gumucio JP2, Flood MD1, Saripalli AL1, Davis ME1, Harning JA1, Lynch EB2, Roche SM1, Bedi A1, Mendias CL3. Am J Sports Med. 2014 Dec;42(12):2860-8. doi: 10.1177/0363546514549943. Epub 2014 Sep 22.
BACKGROUND: The repair and restoration of function after chronic rotator cuff tears are often complicated by muscle atrophy, fibrosis, and fatty degeneration of the diseased muscle. The inflammatory response has been implicated in the development of fatty degeneration after cuff injuries. Licofelone is a novel anti-inflammatory drug that inhibits 5-lipoxygenase (5-LOX), as well as cyclooxygenase (COX)-1 and COX-2 enzymes, which play important roles in inducing inflammation after injuries. While previous studies have demonstrated that nonsteroidal anti-inflammatory drugs and selective inhibitors of COX-2 (coxibs) may prevent the proper healing of muscles and tendons, studies about bone and cartilage have demonstrated that drugs that inhibit 5-LOX concurrently with COX-1 and COX-2 may enhance tissue regeneration.
3.Modulation by licofelone and celecoxib of experimentally induced cancer and preneoplastic lesions in mice exposed to cigarette smoke.
Balansky R, Ganchev G, Iltcheva M, Nikolov M, Maestra SL, Micale RT, D'Agostini F, Steele VE, De Flora S1. Curr Cancer Drug Targets. 2015;15(3):188-95.
Chronic inflammation plays a crucial role in cigarette smoke-related carcinogenesis. Accordingly, anti-inflammatory agents, such as nonsteroidal anti-inflammatory drugs (NSAIDs), provide a rational strategy in cancer chemoprevention. We assayed celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, and licofelone, an inhibitor of COX-1, COX-2, and 5- lipoxygenase (5-LOX), for the ability to modulate carcinogenesis in neonatal mice exposed to mainstream cigarette smoke (MCS) for 4 months and thereafter kept in filtered air for 3.5 months. A preliminary toxicity study and a chemoprevention study involved the use of 591 Swiss H mice. Exposure to MCS caused a variety of pulmonary emphysema, alveolar and bronchial epithelial hyperplasias, proliferation of blood vessels, microadenomas, adenomas and malignant tumors, as well as kidney tubular and urinary bladder papillary epithelial hyperplasias. Celecoxib (1600 mg/kg diet) and even better licofelone (960 mg/kg diet) were able to significantly attenuate the MCS-induced alterations of inflammatory nature, including pulmonary emphysema, alveolar epithelial hyperplasias and microadenomas and urinary tract hyperplastic lesions when given to mice according to a protocol that mimics an intervention in current smokers.
4.Targeting pancreatitis blocks tumor-initiating stem cells and pancreatic cancer progression.
Mohammed A1, Janakiram NB1, Madka V1, Brewer M1, Ritchie RL1, Lightfoot S1, Kumar G1, Sadeghi M1, Patlolla JM1, Yamada HY1, Cruz-Monserrate Z2, May R3, Houchen CW3, Steele VE4, Rao CV1. Oncotarget. 2015 Jun 20;6(17):15524-39.
Recent development of genetically engineered mouse models (GEMs) for pancreatic cancer (PC) that recapitulates human disease progression has helped to identify new strategies to delay/inhibit PC development. We first found that expression of the pancreatic tumor-initiating/cancer stem cells (CSC) marker DclK1 occurs in early stage PC and in both early and late pancreatic intraepithelial neoplasia (PanIN) and that it increases as disease progresses in GEM and also in human PC. Genome-wide next generation sequencing of pancreatic ductal adenocarcinoma (PDAC) from GEM mice revealed significantly increased DclK1 along with inflammatory genes. Genetic ablation of cyclo-oxygenase-2 (COX-2) decreased DclK1 in GEM. Induction of inflammation/pancreatitis with cerulein in GEM mice increased DclK1, and the novel dual COX/5-lipoxygenase (5-LOX) inhibitor licofelone reduced it. Dietary licofelone significantly inhibited the incidence of PDAC and carcinoma in situ with significant inhibition of pancreatic CSCs.